CGAS antagonist compounds

A method for treating a disease or condition responsive to antagonism of cyclic GMP-AMP synthase (cGAS) activity, comprising:

• administering to a patient in need thereof, a therapeutically effective amount of a compound;
• wherein the disease or condition is systemic lupus erythematosus, psoriasis, insulin-dependent diabetes mellitus (IDDM), scleroderma, Aicardi Gourtiers syndrome, dermatomyositis, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome (SS), Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, atherosclerosis, myocardial infarction, cardiovascular disease, senescence, or ocular inflammation;
• and
• wherein the compound is of Formula Ia or is a pharmaceutically acceptable salt thereof:
• wherein:
• X is NH or S;
• Y is O or S;
• Z is O, S, CHR1a or NR1a;
• R1a is hydrogen, C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups;
• G is N or C;
• if G is N, R1 is hydrogen C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups,
• if G is N and if Z includes R1a, R1-R1a is connected as a —CH2CH2—, —CH2CH2CH2—, —CH═CH—, —C(CH3)═CH—, or —CH═C(CH3)— group;
• and
• if G is C and if Z includes R1a, R1-R1a is connected as a ═CH—CH═CH—, ═N—CH═CH—, or ═CH—N═CH— group;
• R1 is hydrogen or C1-6 alkyl, or R1-R1a are connected form a —CH2CH2—, —CH2CH2CH2—, —CH═CH—, —C(CH3)═CH—, or —CH═C(CH3)— group or together with carbon or nitrogen atoms to which they are attached form a pyridine, pyrimidine or pyrazine ring;
• R2 is hydrogen, halogen, C1-6alkyl, or C1-6alkyl selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, or azido groups;
• R2a is phenyl or a heteroaryl group selected from imidazolyl, pyridyl, pyridizinyl, pyrimidinyl, and pyrazinyl, wherein the phenyl or heterocyclic group is optionally substituted with 1-4 substituents independently selected from halogen, —SR3a, —S(O)R3a, —OR3a, —OCH2R3b, —OCH(CH3)R3b, —OC(O)NHR3a, —NR3aR4a, —NHSO2R3a, azido, —CHO, —CO2R3a, cyano, C1-6alkyl, —CR8aR6aR7a, C2-6alkenyl, —C(R5a)═C(R8a)(R9a), C2-6alkynyl, and —C≡CR8a;
• R3a, R3b, and R4a are independently hydrogen, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups, C1-6alkyl, cyclic-(C1-8alkyl)-, cyclic-(C1-6oxaalkyl)-, cyclic-(C1-6azaalkyl)-, C2-6alkenyl, or C2-6alkynyl;
• wherein the phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, and thiazolyl, tetrazolyl groups are optionally substituted with 1-3 substituents independently selected from halogen, thiol, C1-6alkyl thioether, C1-6alkyl sulfoxide, C1-6alkyl, C1-6alkoxyl, amino, C1-6alkylamino, C1-6dialkylamino, C1-6alkyl sulfonamide, azido, —CHO, —CO2H, C1-6alkyl carboxylate, cyano, C2-6alkenyl, and C2-6alkynyl group;
• and the C1-6alkyl, cyclic-(C1-8alkyl)-, cyclic-(C1-6oxaalkyl)-, cyclic-(C1-6azaalkyl)-, C2-6alkenyl, and C2-6alkynyl groups are selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups;
• and
• R5a, R6a, R7a, R8a and R9a are independently hydrogen, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl groups, C1-6alkyl, cyclic-(C1-8alkyl)-, cyclic-(C1-6oxaalkyl)-, cyclic-(C1-6azaalkyl)-, C2-6alkenyl, C2-6alkynyl, C1-6alkoxyl, cyclic —(C1-8 alkoxyl)-, cyclic-(C1-6oxaalkoxyl)-, cyclic-(C1-6azaalkoxyl)-;
• wherein the phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, and thiazolyl, tetrazolyl groups are optionally substituted with 1-3 substituents independently selected from halogen, thiol, C1-6alkyl thioether, C1-6alkyl sulfoxide, C1-6alkyl, C1-6alkoxyl, amino, C1-6alkylamino, C1-6dialkylamino, C1-6alkyl sulfonamide, azido, —CHO, —CO2H, C1-6alkyl carboxylate, cyano, C2-6alkenyl, and C2-6alkynyl group, and the C1-6alkyl, cyclic-(C1-8alkyl)-, cyclic-(C1-6oxaalkyl)-, cyclic-(C1-6azaalkyl)-, C2-6alkenyl, and C2-6alkynyl groups are selectively functionalized with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6alkoxy, C1-6hydroxyalkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, azido, piperidinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, or tetrazolyl groups.